N-terminal variants of thyroid hormone receptor β: Differential function and potential contribution to syndrome of resistance to thyroid hormone

Lily Ng, Douglas Forrest, Bryan R. Haugen, William M. Wood, Tom Curran

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The human syndrome of resistance to thyroid hormone (RTH) is associated with dominant mutations in the thyroid hormone receptor β (TRβ) gene that generate mutant receptors with impaired binding for T3. Although the TRβ gene differentially expresses two N-terminal variant receptors, TRβ1 and TRβ2, functional analyses of RTH mutants have focused exclusively on TRβ1. Since TRβ2 is expressed in tissues that are malfunctional in RTH, the role of mutations in the context of TRβ2 was examined. We compared the functional properties of corresponding RTH mutations in the common C-terminal domain of both TRβ1 and TRβ2. Wild type TRβ1 end TRβ2 bound similarly as homodimers and as heterodimers with retinoid X receptors to T3-responsive elements consisting of a direct repeat with 4-base pair spacing or an everted repeat. Homodimers, but not monomers or heterodimers, of both receptor subtypes were dissociated by the addition of T3. However, TRβ2 formed at least 10-fold more stable homodimers than TRβ1 on a palindromic repeat element, indicating that the N termini of TRβ1 and TRβ2 differentially influence dimerization on DNA. The RTH-like mutants of both TRβ1 and TRβ2 were equally insensitive to T3. They were defective in T3 binding but still bound DNA like their wild type counterparts except that the T3-dependent dissociation of homodimers from DNA was severely reduced. Wild type TRβ1 and TRβ2 mediated T3-inducible transactivation in cotransfection assays; this, however, was abolished in both mutants. TRβ1 mediated more sensitive T3-dependent transcriptional suppression than TRβ2 through the negative T3 response region of the TSHβ gene. Again, the mutation abolished T3-dependent suppression by both mutants. Furthermore, both mutants inhibited T3- inducible transcriptional activation by different wild type TRα and β variants. These results indicate that both mutants have the potential to contribute to the pathogenesis of RTH and suggest that a reassessment of previous models of RTH is required to take into account the inhibitory activity of both TRβ2 and TRβ1 mutants.

Original languageEnglish
Pages (from-to)1202-1213
Number of pages12
JournalMolecular Endocrinology
Volume9
Issue number9
DOIs
StatePublished - Sep 1995
Externally publishedYes

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